Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22 mg/m³
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
2 050 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Converting the oral NOAEL rat into a dermal NOAEL is necessary to derive the correct starting point for the

dermal route for which no study was carried out.

AF for dose response relationship:
1
Justification:
Starting point for the DNEL calculation is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).
AF for differences in duration of exposure:
2
Justification:
A assessment factor 2 is suggested by the ECHA TGD for exposure duration from subchronic to chronic (see section R 8.4.3.1, Table R.8-5) (ECHA, Nov. 2012).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 is suggested by the ECHA TGD (see section 8.4.3.1 of TGD; ECHA, Nov. 2012) for interspecies differences.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is suggested by the ECHA TGD (ECHA, Nov. 2012) for remaining interspecies differences.
AF for intraspecies differences:
5
Justification:
For intraspecies variability, the default assessment factor for worker for systemic effects is 5 (ECHA, Nov. 2012).
AF for the quality of the whole database:
1
Justification:
Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).
AF for remaining uncertainties:
1
Justification:
No further assessment factors are considered necessary.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
41 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Inhalatory exposure

For workers in industrial and professional settings, which are exposed via inhalation, DNELs for acute and long-term inhalation effects of isophorone have to be derived. In addition, the eye and respiratory irritation potential of isophorone have to be assessed.

Regarding to ECHA Guidance, Chapter R.8, Appendix R.8 -13 in cases where toxicological information and evaluations of health effects used for setting a national OEL are documented and available, this may be used and taken into account in deriving the DNEL.

The current legally binding German occupational exposure limit (TRGS 900) is 11 mg/m3 (2 ppm) (Technical Rule for Hazardous Substances 900, German Federal Ministry of Labour and Social Affairs).

This value covers the repeated and acute inhalation toxicity, the irritation potential, and the carcinogenicity of isophorone (isophorone is not a genotoxic carcinogen), as the local effects at the eyes and the respiratory tract are the most sensitive effects.

On the basis of following data a ceiling limit of 2 ppm for isophorone is recommended. These data are well documented and available, they are valid and acceptable for assessment. Another data for isophorone are not present.

Effects on humans

Acute

Groups of 11 or 12 subjects exposed for a few minutes to atmospheric isophorone concentrations of 40, 85, 200 and 400 ppm experienced irritation of the eyes, nose and throat (Smyth and Seaton, 1940; see chapter 7.10.5 in IUCLID 5). A few complaints of nausea, headache, dizziness, faintness, inebriation and a feeling of suffocation occurred at concentrations of 200 and 400 ppm. The symptoms of irritation and narcosis were said to be less intensive following exposure to atmospheres containing 40 to 85 ppm.

Subchronic

Complaints of faitigue and malaise were reported among workers exposed for 1 month to atmospheres containing 28.5 to 48 mg isophorone/m3 (5 to 8 ppm) isophorone (Ware, 1973; see chapter 7.10.5 in IUCLID 5). No further complaints were received following a reduction of the concentration to between 5.7 and 23 mg/m3 (1 and 4 ppm). On the basis of these data the American Conference of Governmental Industrial Hygienists (ACGIH) recommended a ceiling limit of 5 ppm for isophorone.

Eye and respiratory irritation

Smyth and seaton (1940) reported eye, nose and throat irritation following exposure to isophorone levels of 40, 85, 200 and 400 ppm for a few minutes. At 40 and 85 ppm the initial irritation did not persist throughout the exposure.

Silverman et al. (1946; see chapter 7.10.5. in IUCLID 5) estimated the sensory threshold of a number of ketones including isophorone. An average of 12 subjects of both sexes were used for each solvent exposure. The time of exposure was 15 minutes. Irritation of the eyes, nose and throat was experienced at 25 ppm isophorone. 40 % of the exposed subjects objected isophorone odor at a concentration of 58 mg/m3 (10 ppm), and this concentration was judged to be the highest tolerable air level for 8 hour exposure.

Effects on animals

In a study with 6 weeks (8 hours/day, 5 days/week) duration, at doses >= 287 mg/m3(50 ppm) congested kidneys, dilated Bowman´s capsules and lung changes (irritation, congestion) were found in rats and guinea pigs (Smyth et al., 1942; see chapter 7.5.3 in IUCLID 5). At doses of 25 ppm (144 mg/m3) isophorone no effects were observed.

In rats exposed for 4 weeks (6 hours/day, 5 days/week) to 208 mg isophorone/m3reduced body weights and decreased liver weights in males and changes in heamatological parameters in females were found (NOAEC (rat, 28 days) < 208 mg/m3 or < 36 ppm) (Exxon, 1968; see chapter 7.5.3 in IUCLID 5).

Therefore, concerning the irritant effects in humans and the observed effects in animals studies (eye and nose irritation; blood and liver changes) an occupational exposure limit of 11 mg/m3 (2 ppm) was derived. This value is in line with other DNEL values derived from acute and long-term inhalation studies (calculations see below) and with the eye and respiratory irritation potential of isophorone, leading to a

Worker-DNEL long-term for inhalation route - local effects = 11 mg/m3

and a

Worker-DNEL long-term for inhalation route - systemic effects = 11 mg/m3

Calculations for inhalation exposure

(1) Conversion of an rat LOAECinhalatory; rep. dosefrom 28 day rat inhalativ repeated dose toxicity study into an corrected LOAECinhalatory; rep. dose (derived from figure R.8-2; Chapter R 8.4.2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health”):

 

For workers:

assumptions:

           8h exposure/day

           Inhalation absorption rat = inhalation absorption human

 

corrected LOAECinhalatory; rep.dose        = rat LOAECinhalatory; rep. dose* ((6 h/d) / (8 h/d)) * (6.7 m3(8h) / 10 m3(8h))

                                                                 = 208 mg/m3* 0.75 * 0.67

                                                                 = 104.52 mg/m3

 

Selected assessment factors (according to Table R 8-6 of the TGD): 
               - Interspecies: factor for allometric scaling (systemic)                1*
               - Interspecies: remaining differences (systemic)                         2.5

               - Intraspecies (worker, systemic)                                             5**

               - Exposure duration (systemic; subacute to chronic)                 1***

               - Dose-response (systemic)                                                     3****
               - Quality of the database (systemic; overall)                             1*****

              overall Assessment Factor (overall AF)                                     37.5

* According to ECHA TGD an allometric scaling factor is not applicable when setting an inhalation DNEL based on an inhalation animal study (see Appendix R.8-2), therefore AF 1 is chosen.

** For intraspecies variability, the default assessment factor for workers is 5.

*** The assessment factor suggested by the ECHA TGD for exposure duration from subacute to chronic should be 6, but extrapolation factors for differences in duration of exposure are not always reasonable. In the depicted case the lowest relevant LOAEC-value = 208 mg/m3, derived from a subacute inhalation study in rats. All other observed LOAEC-values derived from subchronic and chronic inhalation studies were determined to be > 208 mg/m3. (LOAECchronic, rat and rabbit = 1436 mg/m3; LOAECsubchronic, rat = 2873 mg/m3; NOAECfertility, rat > 2873 mg/m3; NOAECteratogen, rat> 664 mg/m3)

On this basis it is not expected that a longer duration of the study would change the outcome and an AF of 1 is warranted.

**** Starting point is a LOAEC. Thus standard assessment factor 3 is used as described in chapter R 8.4.3.1 of TGD

***** Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

(2) Conversion of an rat NOAELinhalatory; fertilityfrom fertility toxicity study into an corrected NOAECinhalatory; fertility(derived from figure R.8-2; Chapter R 8.4.2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health”):


For workers:
assumptions:

           8h exposure/d

           Inhalation absorption rat = inhalation absorption human

 

corrected NOAECinhalatory;fertility;male/female= rat NOAECinhalatory; fertility;male/female * ((6 h/d) / (8 h/d)) * (6.7 m3(8h) /10 m3 (8h))  = > 2873 mg/m3* 0.75 * 0.67  = > 1444 mg/m3

Selected assessment factors (according to Table R 8-6 of the TGD): 
                - Interspecies: factor for allometric scaling (systemic)               1*
                - Interspecies: remaining differences (systemic)                         2.5

               - Intraspecies (systemic)                                                           5**

               - Exposure duration (systemic; subchronic to chronic)                2

               - Dose-response (systemic)                                                      1***
                - Quality of the database (systemic; overall)                              1****

               
              overall Assessment Factor (overall AF)                                       25

 

*  According to ECHA TGD an allometric scaling factor is not applicable when setting an inhalation DNEL based on an inhalation animal study (see Appendix R.8-2), therefore AF 1 is chosen.

**For intraspecies variability, the default assessment factor for workers is 5.
 *** Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**** Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

   

(3) Conversion of an rat NOAECinhalatory; developfrom developmental toxicity study into an corrected NOAECinhalatory; develop(derived from figure R.8-2; Chapter R 8.4.2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health”):


For workers:
assumptions:

           8h exposure/d

           Inhalation absorption rat = inhalation absorption human

 corrected NOAECinhalatory;develop= rat NOAECinhalatory; develop*((6 h/d) / (8 h/d)) * (6.7 m3(8h) / 10 m3(8h))

                     = > 664 mg/m3* 0.75 * 0.67

                       = > 334 mg/m3

Selected assessment factors (according to Table R 8-6 of the TGD): 
                - Interspecies: factor for allometric scaling (systemic)               1*
                - Interspecies: remaining differences (systemic)                        2.5

- Intraspecies (systemic)                                                         10**

                - Exposure duration (systemic; subchronic to chronic)              1

                - Dose-response (systemic)                                                     1***
                - Quality of the database (systemic; overall)                              1****

               
              overall Assessment Factor (overall AF)                                      25

 

*  According to ECHA TGD an allometric scaling factor is not applicable when setting an inhalation DNEL based on an inhalation animal study (see Appendix R.8-2), therefore AF 1 is chosen.

**According to TGD Appendix R 8-12: Pregnant women have to be considered as a more vulnerable
 population. When deciding on assessment factors for the DNELdevelopcalculation the developing
 offspring should be the focus of attention. Therefore intraspecies factor of 5 for workers is
 enhanced 2-fold resulting in an assessment factor of 10.

*** Starting point is a NOAEC. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**** Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

***** The exposure and the scope of the animal OECD 414 study is limited to the prenatal stadium and thus it has to be considered to be a chronic exposure for the unborn foetus, which is the focus of attention in this study and regarding the derivation of the DNELdevelop. Thus extrapolation of duration of exposure is not needed and assessment factor is set on 1.

(4) Conversion of an rat LOAELoral; cancer from carcinogenicity study into an corrected LOAECinhalatory; cancer(derived from figure R.8-3; Chapter R 8.4.2 of TGD “Chapter R.8” and example B 3 of Appendix R 8-2 of TGD)

 

For workers:
assumptions:

 - 8h exposure/d

- (ABSoral-rat/ ABSinh-human) = 0.5 (according to Ad 2 of Chapter 8.4.2 of TGD) 

corrected LOAECinhalatory; cancer= rat LOAELoral; cancer * (1 / sRVrat) * (ABSoral-rat/ ABSinh-human) * 

(sRVhuman/wRV)

                    = 500 mg/kg bw d * (1/ 0.38 m3/kg bw d) * 0.5 * (6.7 m3 (8h) / 10 m3 (8h))

                    = 440 mg/m3

Selected assessment factors (according to Table R 8-6 of the TGD): 
                - Interspecies: factor for allometric scaling (systemic)                1*
               - Interspecies: remaining differences (systemic)                          2.5

                - Intraspecies (systemic)                                                            5**

                - Exposure duration (systemic; chronic)                                     1

               - Dose-response (systemic)                                                       3***
                  - Quality of the database (systemic; overall)                        1****

              overall Assessment Factor (overall AF)                                        37.5

 

*  see example B 3 of Appendix R 8-2 of TGD

**For intraspecies variability, the default assessment factor for workers is 5.

*** Starting point is a LOAEC. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**** Because of good/standard quality of the database the standard assessment factor 3 is used as described in chapter R 8.4.3.1 of TGD

(5) Conversion of an rat LOAECinhalatory; rep. dosefrom 18 months rat inhalativ repeated dose toxicity study into an corrected LOAECinhalatory; rep. dose  (local effects) (derived from figure R.8-2; Chapter R 8.4.2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health”):

 

For workers:

assumptions:

           8h exposure/day

           Inhalation absorption rat = inhalation absorption human

 

corrected LOAECinhalatory; rep.dose        = rat LOAECinhalatory; rep. dose* ((6 h/d) / (8 h/d)) * (6.7 m3(8h) / 10 m3(8h))

                                                                 = 1436 mg/m3* 0.75 * 0.67

                                                                  = 721.6 mg/m3

                                                                                           

Selected assessment factors (according to Table R 8-6 of the TGD): 
               - Interspecies: factor for allometric scaling (local)                       1*
               - Interspecies: remaining differences (local)                                 2.5

               - Intraspecies (worker, local)                                                     5**

               - Exposure duration (local; chronic)                                            1

               - Dose-response (local)                                                              3***
                               - Quality of the database (local; overall)                      1****

              overall Assessment Factor (overall AF)                                        37.5

* According to the ECHA TGD allometric scaling should not be applied for local effects on eyes, since these effects are independent of the basal metabolic rate, therefore AF 1 is chosen.

** For intraspecies variability, the default assessment factor for workers is 5.

*** Starting point is a LOAEC. Thus standard assessment factor 3 is used as described in chapter R8.4.3.1 of TGD.

**** Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD.

(6) Derivation of a DNELshort-term extrapolated from the DNEL long-term (according to ECHA Guidance, Chapter R.8., Appendix R. 8 -8, Box 6)

According to the German rule for OELs (Technical Rule for Hazardous Substances 900, German Federal Ministry of Labour and Social Affairs, 2006/2009) for short-term ceiling concentrations an exposure limit could be established by multiplication of an occupational exposure limit (Arbeitsplatzgrenzwert) to an exceeding factor (Überschreitungsfaktor), which is set per default 1, but can be adjusted up to the value of 8 in maximum. For isophorone an factor of 2 is applied, as even a short time exceeding up to 4 ppm (22 mg/m3) does not lead to local irritations that were only reported for higher concentrations.

Worker-DNELacute for inhalation route - local effects = 22 mg/m3

Worker-DNELacutefor inhalation route - systemic effects = 22 mg/m3

Dermal exposure

Additionally, for workers in industrial and professional settings, which are exposed via dermal contact, DNELs for systemic, acute and long-term dermal effects of isophorone have to be derived. No indications of local toxicity were found within several long- and short-term toxicity studies.

(7) Conversion of an rat NOAELoral; rep. dosefrom 90 day rat oral repeated dose toxicity study into an corrected NOAELderm; rep. dose (derived from example B.5; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health”):

 

For worker:

assumptions:

-         absorptionoral-rat= 100% (see Ad 2 of chapter R 8.4.2 of TGD)

-         substance-specific data on dermal absorption for isophorone are available (see chapter 7.1.2 of IUCLID 5): In an in-vitro dermal absorption study with human skin disks the total amount absorbed was less than 5% even after exposure for 24 hours.

-         Absorptiondermal-human= 5%

 

 

corrected NOAELderm; rep.dose= rat NOAELoral; rep. dose* (ABSoral-rat/ ABSderm-human)

                                                                              

                                               = 102.5 mg/kg bw day * (100% / 5%)

 

                                               = 2050 mg/kg bw day

(8) Derivation of a DNELshort-term extrapolated from the DNEL long-term (according to ECHA Guidance, Chapter R.8., Appendix R. 8 -8, Box 6)

For worker:

According to the German rule for OELs (Technical Rule for Hazardous Substances 900, German Federal Ministry of Labour and Social Affairs, 2006/2009) for short-term ceiling concentrations an exposure limit could be established by multiplication of an occupational exposure limit (Arbeitsplatzgrenzwert) to an exceeding factor (Überschreitungsfaktor), which is set per default 1 and could be adjusted to max 8. For isophorone an factor of 2 is applied, as even a short time exceeding up to 41 mg/kg bw day does not lead to systemic dermal effects in the acute dermal studies.

Worker-DNELacutefor dermal route - systemic effects = 41 mg/kg bw day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
LOAEC
Value:
52 mg/m³
Explanation for the modification of the dose descriptor starting point:
No route-to-route-extrapolation needed
AF for dose response relationship:
3
Justification:
Starting point is a LOAEC. Thus standard assessment factor 3 is used as described in chapter R 8.4.3.1 of ECHA TGD (ECHA, Nov. 2012).
AF for differences in duration of exposure:
1
Justification:
The assessment factor suggested by the ECHA TGD for exposure duration from subacute to chronic should be 6, but extrapolation factors for differences in duration of exposure are not always reasonable. In the depicted case the lowest relevant LOAEC value is 208 mg/m3, derived from a subacute inhalation study in rats. All other observed LOAEC values derived from subchronic and chronic inhalation studies were determined to be > 208 mg/m3. (LOAEC chronic, rat and rabbit = 1436 mg/m3; LOAEC subchronic, rat = 2873 mg/m3; NOAEC fertility, rat > 2873 mg/m3; NOAEC teratogen, rat > 664 mg/m3) On this basis it is not expected that a longer duration of the study would change the outcome and an AF of 1 is warranted.
AF for interspecies differences (allometric scaling):
1
Justification:
According to ECHA TGD (ECHA, Nov. 2012) an allometric scaling factor is not applicable when setting an inhalation DNEL based on an inhalation animal study (see Appendix R.8-2), therefore AF 1 is chosen.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is suggested by the ECHA TGD (ECHA, Nov. 2012) for remaining interspecies differences
AF for intraspecies differences:
10
Justification:
For intraspecies variability, the default assessment factor for general population for systemic effects is 10 (ECHA, Nov. 2012).
AF for the quality of the whole database:
1
Justification:
Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of ECHA TGD (ECHA, Nov. 2012).
AF for remaining uncertainties:
1
Justification:
No further assessment factors are considered necessary.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.512 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
102.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route-to-route-extrapolation needed
AF for dose response relationship:
1
Justification:
Starting point for the DNEL calculation is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).
AF for differences in duration of exposure:
2
Justification:
A assessment factor 2 is suggested by the ECHA TGD for exposure duration from subchronic to chronic (see section R 8.4.3.1, Table R.8-5) (ECHA, Nov. 2012).
AF for interspecies differences (allometric scaling):
4
Justification:
An allometric scaling factor of 4 is suggested by the ECHA TGD (see section 8.4.3.1 of TGD; ECHA, Nov. 2012) for interspecies differences.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 is suggested by the ECHA TGD (ECHA, Nov. 2012) for remaining interspecies differences.
AF for intraspecies differences:
10
Justification:
For intraspecies variability, the default assessment factor for the general population is 10 (ECHA, Nov. 2012).
AF for the quality of the whole database:
1
Justification:
Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).
AF for remaining uncertainties:
1
Justification:
No further assessment factors are considered necessary.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.512 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Isophorone is exclusively used as a solvent for resins, polymers and pesticides formulations. A direct use of this substance is not known. The exposure of consumers to isophorone is unlikely to occur via consumer products, because no consumer product is known to contain isophorone.

An exposure of the general population via the environment might occur through ingestion of foodstuff or drinking water, that came in contact with isophorone via the use as solvent for agrochemicals. Bystanders and residents can also be exposed to the mixture containing isophorone during professional spraying in agrochemical use.

Therefore, an oral and inhalation DNEL for general population is derived.

Furthermore, a risk assessment for bystanders and residents for agrochemical uses is provided in this CSR (see section 9.7).

Nevertheless isophorone released to the environment would rapidly be degraded in water and photooxidants. Additionally, in view of low toxicity in experimental studies and low levels of exposure from environment sources, the risk to the general population appears to be minimal.

(1) Conversion of an rat LOAECinhalatory; rep. dosefrom 28 day rat inhalativ repeated dose toxicity study into an corrected LOAECinhalatory; rep. dose (derived from figure R.8-2; Chapter R 8.4.2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health”):

 

For general population:

assumptions:

24 h exposure/day

Inhalation absorption rat = inhalation absorption human

 

corrected LOAECinhalatory; rep.dose        = rat LOAECinhalatory; rep. dose* ((6 h/d) / (24 h/d))

                                                                               = 208 mg/m3* 0.25

                                                                               = 52 mg/m3

(2) Conversion of an rat NOAELoral; rep. dosefrom 90 day rat oral repeated dose toxicity study into an humanNOAELoral; rep. dose (derived from example A.1; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health”):

 

For general population:

assumptions:

absorptionoral-rat= absorptionoral-human

 

human NOAELoral; rep.dose= rat NOAELoral; rep. dose   = 102.5 mg/kg bw day